Epidemiological studies on the association of estrogen treatment and cancer in postmenopausal women indicate a clear need for basic investigations of the carcinogenic potential of different types of estrogenic hormone. The objectives of this research program are to establish the mutagenic and carcinogenic potential of the metabolic activation products of important natural estrogens and specific synthetic estrogenic hormones of current therapeutic interest. These objectives will be accomplished using in vitro mammalian cell culture systems, including a selected group of lines of human endometrial origin which are of greatest significance to this program. Our working hypothesis is that the carcinogenic potential of these estrogens will correlate with their rates of metabolic activation. This hypothesis is supported by the results obtained to date, and will be further tested by studies designed to delineate the basic mechanism(s) involved in the malignant transformation induced in the selected cell lines by metabolically activated estrogens. The effects of these metabolic activation products will be examined in Balb/c 3T3 cells to determine induction of DNA repair replication, chromatid-type chromosomal aberrations, sister chromatid exchanges, and chemical transformation in this carcinogen-transformable cell line. If our hypothesis is supported by further results from one or more of these cellular assays, it will provide a major insight into the mechanism of carcinogenesis associated with certain estrogens.